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Chapter 10: Disorders of Sex Development

John C. Achermann; J. Larry Jameson

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INTRODUCTION

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Sex development begins in utero but continues into young adulthood with the achievement of sexual maturity and reproductive capability. The major determinants of sex development can be divided into three components: chromosomal sex, gonadal sex (sex determination), and phenotypic sex (sex differentiation) (Fig. 10-1). Variations at each of these stages can result in disorders (or differences) of sex development (DSDs) (Table 10-1). In the newborn period, approximately 1 in 4000 babies require investigation because of ambiguous (atypical) genitalia. Urgent assessment is required, because some causes such as congenital adrenal hyperplasia (CAH) can be associated with life-threatening adrenal crises. Support for the parents and clear communication about the diagnosis and management options are essential. The involvement of an experienced multidisciplinary team is important for counseling, planning appropriate investigations, and discussing long-term well-being. DSDs can also present at other ages and to a range of health professionals. Subtler forms of gonadal dysfunction (e.g., Klinefelter’s syndrome [KS], Turner’s syndrome [TS]) often are diagnosed later in life by internists. Because these conditions are associated with a variety of psychological, reproductive, and potential medical consequences, an open dialogue must be established between the patient and health care providers to ensure continuity and attention to these issues.

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FIGURE 10-1

Sex development can be divided into three major components: chromosomal sex, gonadal sex, and phenotypic sex. DHT, dihydrotestosterone; MIS, müllerian-inhibiting substance also known as anti-müllerian hormone, AMH; T, testosterone.

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TABLE 10-1Classification of Disorders of Sex Development (DSDs)
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TABLE 10-1 Classification of Disorders of Sex Development (DSDs)
SEX CHROMOSOME DSD 46,XY DSD (SEE TABLE 10-3) 46,XX DSD (SEE TABLE 10-4)

47,XXY (Klinefelter’s syndrome and variants)

45,X (Turner’s syndrome and variants)

45,X/46,XY mosaicism (mixed gonadal dysgenesis)

46,XX/46,XY (chimerism/mosaicism)

Disorders of gonadal (testis) development

Complete or partial gonadal dysgenesis (e.g., SRY, SOX9, SF1, WT1, DHH, MAP3K1)

Impaired fetal Leydig cell function (e.g., SF1/NR5A1, CXorf6/MAMLD1)

Ovotesticular DSD

Testis regression

Disorders in androgen synthesis or action

Disorders of androgen biosynthesis

 LH receptor (LHCGR)

 Smith-Lemli-Opitz syndrome

 Steroidogenic acute regulatory (StAR) protein

 Cholesterol side-chain cleavage (CYP11A1)

 3β-Hydroxysteroid dehydrogenase II (HSD3B2)

 17α-Hydroxylase/17,20-lyase (CYP17A1)

 P450 oxidoreductase (POR)

 Cytochrome b5 (CYB5A)

 17β-Hydroxysteroid dehydrogenase III (HSD17B3)

 5α-Reductase II (SRD5A2)

 Aldo-keto reductase 1C2 (AKR1C2)

Disorders of androgen action

 Androgen insensitivity syndrome

 Drugs and environmental modulators

Other

Syndromic associations of male genital development

Persistent müllerian duct syndrome

Vanishing testis syndrome

Isolated hypospadias

Congenital hypogonadotropic hypogonadism

Cryptorchidism

Environmental influences

Disorders of gonadal (ovary) development

Gonadal dysgenesis

Ovotesticular DSD

Testicular DSD (e.g., SRY+, dup SOX9, RSPO1)

Androgen excess

Fetal

 3β-Hydroxysteroid dehydrogenase II (HSD3β2)

 21-Hydroxylase (CYP21A2)

 P450 oxidoreductase (POR)

 11β-Hydroxylase (CYP11B1)

 Glucocorticoid receptor mutations

Fetoplacental

 Aromatase ...

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